The American Journal of Medicine
Volume 121, Issue 6 , Pages 525-531, June 2008

Racial and Ethnic Variations in Hepatocellular Carcinoma Incidence within the United States

  • Robert Wong, MD

      Affiliations

    • University of California, San Francisco School of Medicine, San Francisco
    • Corresponding Author InformationRequests for reprints should be addressed to Robert Wong, University of California, San Francisco, School of Medicine, 4306 Saint Cloud Court, Oakland, CA 94619.
    • ,
  • Douglas A. Corley, MD, PhD, MPH

      Affiliations

    • Northern California Division of Research, Oakland
    • Division of Gastroenterology, Department of Medicine, University of California, San Francisco.

Article Outline

Abstract 

Background

The increasing incidence of hepatocellular carcinoma coupled with this cancer's high mortality is a public health problem. Delineating high-risk populations and cancer patterns can provide valuable information. This is necessary to broaden screening and surveillance guidelines related to early detection and prevention.

Methods

By using data collected by the Surveillance, Epidemiology, and End Results program, a population-based cancer registry in the United States, our retrospective cohort study evaluated sex-specific, race/ethnicity-specific, and age-specific variations in hepatocellular carcinoma incidence from 1992 to 2004.

Results

With men and women combined, the incidence of hepatocellular carcinoma among Asians was the highest, nearly double that of white Hispanics (11.0 vs 6.8 per 100,000/y), and more than 4 times higher than that of Caucasians (11.0 vs 2.6 per 100,000/y). Although male subjects demonstrated a doubling of cancer rates every 10 years from 30 to 50 years of age, female subjects reached male-comparable rates of cancer 10 to 15 years later and peaked at significantly lower values for all race and ethnic groups.

Conclusion

Marked differences in the incidence rates of hepatocellular carcinoma by sex, ethnicity, and age of diagnosis likely represent variations in risk factor distributions (eg, viral hepatitis) and possibly in host genetics or other environmental factors. An individualized approach tailored to specific risk profiles may more effectively identify treatable tumors than more general guidelines.

Keywords: Burden of disease, Hepatitis, Multiethnic disparities, Primary liver cancer, Screening and surveillance

 

Primary liver cancer is the sixth most common cancer worldwide and the third most common cause of death from cancer.1 Hepatocellular carcinoma accounts for 85% to 90% of primary liver cancers.2 Although the incidence of hepatocellular carcinoma is greatest in Asia and Africa, it is rapidly increasing in the United States.3, 4, 5, 6, 7 The health impact of the increasing incidence is compounded by poor prognoses; overall 1- and 5-year survival times are 23% and 5%, respectively.8, 9, 10 These findings underscore the importance of delineating high-risk populations and cancer patterns to facilitate the development of effective screening and surveillance programs.

Clinical Significance

 


•Significant sex-specific, age-specific, and race/ethnicity-specific variations in hepatocellular carcinoma incidence exist.

•Screening and surveillance programs targeted to individual risk profiles can identify treatable tumors more efficaciously, minimizing interventions in patients with lower risks.

•Observed disparities in hepatocellular carcinoma's burden of disease provides opportunities to more effectively use limited health care resources.

Current clinical guidelines recommend initiating hepatocellular carcinoma screening in some high-risk groups, but little data are available in the United States regarding how cancer incidence may differ by age and race/ethnicity. Recent studies have reported age-adjusted rates of hepatocellular carcinoma in the United States doubling during the past 2 decades, proposing that heterogeneity may exist in the factors influencing these rates.11, 12, 13, 14, 15 However, current screening and surveillance programs are largely based on broad categoric risk groups that are insufficient to address this heterogeneity. Consensus on the optimal periods to initiate screening in various risk groups is lacking, limiting the success of current guidelines in early detection and prevention.16, 17, 18, 19, 20 Knowledge of age-specific, sex-specific, and race-specific incidence rates would inform guidelines related to the initiation of cancer screening and surveillance and facilitate research on the effectiveness of these interventions.

In our analysis, we examined the age-specific, sex-specific, and race-specific variability of hepatocellular carcinoma incidence using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) cancer registry. We compared the observed differences in cancer rates between demographic groups and correlated these findings with population data to determine the burden of disease distribution for each group.

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Materials and Methods 

Data Sources 

Data were obtained from a population-based cancer registry covering approximately 26% of the US population: the SEER program. Before 1992, SEER used “white,” “black,” and “other” race classifications. From 1992 to 2004, expanded race classifications were included: whites, blacks, Asian/Pacific Islanders, American Indian/Alaskan Natives, and Hispanic ethnicity; thus our analyses were performed for this interval. The 1992 to 2004 data set includes data from 10 states: Georgia, Connecticut, Michigan, Hawaii, Iowa, New Mexico, California, Washington, Utah, and Alaska.10, 21

Definitions 

SEER identifies hepatocellular carcinoma cases with pathologic or histologic verification using the International Classification of Disease for Oncology, 3rd edition.22, 23 Our analyses used SEER's expanded race and ethnic categories: non-Hispanic whites (Caucasians), blacks, American Indians/Alaskans, Asian/Pacific Islanders (Asians), and white Hispanics. Small numbers of cancer cases among other Hispanic groups (black Hispanics, Asian/Pacific Islander Hispanics, American Indian/Alaskan Hispanics) precluded the calculation of precise estimates for these populations. Cancer staging definitions were based on the SEER staging system, which is unique to the SEER database and used primarily for describing the extent of disease, and not necessarily for prognostic determination. Localized cancers are confined to 1 lobe of the liver. Regional cancers include more than 1 lobe involved via contiguous growth of a single lesion; extension to the diaphragm, extrahepatic bile ducts, or gallbladder; or regional lymph node involvement. Distant cancers include metastatic disease; extension of cancer to the pancreas, pleura, or stomach; or distant lymph node involvement.23 Our study focused on localized and distant stages of disease.

Statistical Analysis 

All analyses were performed using the SEER*Stat 6.5.3 statistical package (National Cancer Institute, Bethesda, Md) and Open Office 1.1.4, an open source office productivity suite (Sun Microsystems, Santa Clara, Calif). P values for the differences between rates were calculated with the z statistic using standard equations.24 Annual incidence rates are per 100,000 and were age adjusted to the US standard population of 2000. Age-specific incidence rates were calculated on the basis of 5-year age groups to enhance precision of the estimates. Calendar year-specific rates were calculated on the basis of 2-year averages, with the exception of the final interval being a 3-year average because of the odd number of years available for inclusion.

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Results 

Overview 

From the 1992 to 2004 dataset, 18,442 cases of hepatocellular carcinoma were identified (13,533 male cases, 4909 female cases). Table 1 presents the incidence rate and cancer distribution among race/ethnicity and stage classifications (“all stages” includes localized, regional, and distant stages of disease). Hepatocellular carcinoma incidence rates showed significant variation by sex and ethnicity (Table 1).

Table 1. Average Incidence Rates of Hepatocellular Carcinoma per 100,000 Population, 1992-2004
All StagesLocalized StageDistant Stage
Rate (count)95% CIRate (count)95% CIRate (count)95% CI
Male
All race/ethnic groups6.7(13533)(6.6-6.8)2.3(4700)(2.3-2.4)1.2(2542)(1.2-1.3)
Caucasian4.3(6079)(4.2-4.4)1.5(2171)(1.5-1.6)0.8(1137)(0.8-0.8)
Black9.2(1585)(8.8-9.7)2.9(487)(2.6-3.2)2.0(352)(1.8-2.3)
American Indian/Alaskan6.6(128)(5.4-8.0)3.0(58)(2.2-3.9)1.2(21)(0.7-1.9)
Asian or Pacific Islander17.5(3577)(16.9-18.1)6.1(1236)(5.7-6.4)3.0(627)(2.8-3.2)
White Hispanic11.1(2099)(10.6-11.7)3.8(730)(3.5-4.1)2.0(394)(1.8-2.2)
Female
All race/ethnic groups2.0(4909)(1.9-2.0)0.8(1893)(0.7-0.8)0.3(839)(0.3-0.4)
Caucasian1.2(2154)(1.2-1.3)0.4(800)(0.4-0.5)0.2(382)(0.2-0.2)
Black2.5(536)(2.3-2.7)0.9(184)(0.7-1.0)0.5(102)(0.4-0.6)
American Indian/Alaskan3.2(71)(2.5-4.1)1.5(33)(1.0-2.1)0.6(12)(0.3-1.1)
Asian or Pacific Islander5.7(1393)(5.4-6.0)2.3(565)(2.1-2.5)0.9(214)(0.8-1.0)
White Hispanic3.4(735)(3.2-3.7)1.4(305)(1.2-1.5)0.6(125)(0.5-0.7)
Male and Female
All race/ethnic groups4.1(18442)(4.1-4.2)1.5(6593)(1.4-1.5)0.8(3381)(0.7-0.8)

Annual incidence rates were age-standardized to U.S. population of 2000 and are stratified by year, stage, gender, and ethnicity. “All stages” refers to localized, regional, distant stages, and unstaged cancers combined. Localized stages refer to cancers confined to one lobe of the liver. Distant stages refers to metastatic disease, extension of cancer to pancreas, pleura, or stomach, or evidence of distant lymph node involvement. Note: Regional stage and unstaged cancers were not included as a separate category. Other Hispanic groups (black Hispanics, Asian/PI Hispanics, AI/Alaskan Hispanics) were not included as separate race/ethnic categories, but are included in the all race groups combined category.

Sex and Race/Ethnicity Differences 

Among male and female subjects combined, the incidence rate among Asians was nearly double that of white Hispanics, the next closest group (11.0 vs 6.8 per 100,000/y; P<.0001), and more than 4 times higher than that of Caucasians (11.0 vs 2.6 per 100,000/y; P<.0001).

Incidence rates were markedly higher in male than female subjects for all race/ethnic categories (Table 1). Among men, the rate in Asians was approximately 60% higher than that of white Hispanics (17.5 vs 11.1 per 100,000/y; P<.0001) and more than 4 times higher than that of Caucasians (17.5 vs 4.3 per 100,000/y; P<.0001). The rate in blacks more than doubled that of Caucasians (9.2 vs 4.3 per 100,000/y; P<.0001). Among women, similar patterns were seen, with the rates among Asians more than 4 times that of Caucasians, the group with the lowest rate (5.7 vs 1.2 per 100,000/y; P<.0001).

Age-Specific Differences 

The incidence rate of hepatocellular carcinoma increased with age among all groups, peaking in the eighth decade (Figure 1); however, the trends differed by sex and race (Figure 1A, B). The incidence rate among Asian men started increasing at approximately age 35 to 39 years, reaching more than 20 per 100,000/y by age 45 to 49 years and more than 80 per 100,000/y by age 75 to 79 years. In contrast, the incidence among Caucasian men did not achieve an incidence of 20 per 100,000/y until age 75 years and never exceeded 30 per 100,000/y. The rate among white Hispanics, although lower than Asians, also demonstrated a significant upward trend: 0.2 (30-34 years), 3.5 (40-44 years), 18.8 (50-54 years), and 31.7 (60-64 years) per 100,000/y. Although the incidence rate among black men followed the trend for white Hispanics, the rate plateaued in the mid-late seventh decade; in contrast, the rate among white Hispanics continued to increase and peaked in the mid-eighth decade. Although rates in Caucasians and American Indian/Alaskans also demonstrated similar age-specific trends, their absolute rates were lower than other groups.

  • View full-size image.
  • Figure 1. 

    Age-specific incidence rates of hepatocellular carcinoma in (A) men and (B) women. Incidence rates are per 100,000 population per year and are stratified by ethnicity for the 1992 to 2004 study period.

The overall order of cancer rates among women was similar to among men, but women reached male-comparable levels 10 to 15 years later and peaked at significantly lower values. For example, the incidence rates among Caucasian women (4.4 per 100,000/y at 65-69 years) reached comparable rates 2 decades later than Caucasian men (4.2 per 100,000/y at 45-49 years). Similar variations were seen in other race categories.

Stage of Disease Distribution 

The proportion of localized and distant stages of cancers was calculated by dividing each by the total number of cancer cases. Among men and women combined, the proportion of localized cancers (35.7%) was twice as high as distant cancers (18.3%) (Table 1). The stage distribution was similar between men (localized 34.7%, distant 18.8%) and women (localized 38.6%, distant 17.1%). The relative distribution of localized and distant disease also was similar by race/ethnicity (Table 1).

Temporal Trends 

Considerable increases in incidence during the relatively brief 12-year interval was observed (Figure 2). During this period, white Hispanics (+55%) and blacks (+52%) showed the greatest relative increase; Asians showed a smaller relative increase (+16%) and a greater absolute increase. The greatest absolute increase was among white Hispanics (from 4.9 to 7.6 per 100,000/y). Although Caucasians demonstrated a 50% increase in incidence rate, they experienced the smallest absolute increase.

  • View full-size image.
  • Figure 2. 

    Age-standardized incidence rates of hepatocellular carcinoma by ethnicity and year. Incidence rates are per 100,000 population and are presented by 2-year averages from 1992 to 2004. The final category is a 3-year average because of the odd number of years available for inclusion. P values from trend analysis using SEER statistical package is reported.

Relative Burden of Disease Distribution 

Figure 3 presents the relative distribution of hepatocellular carcinoma among ethnic groups and compares this with each group's representation in the population from 1992 to 2004. The majority of cancer cases were in Caucasians because it was the largest demographic group in the study; proportionally, the relative burden of disease among Caucasians was lower than others. In contrast, the relative burden of disease was much higher among Asians, who accounted for more than a quarter of all cancer cases while comprising only 10.8% of the population.

  • View full-size image.
  • Figure 3. 

    Relative burden of disease distribution of hepatocellular carcinoma. The relative distribution of hepatocellular carcinoma among race/ethnic groups is compared with the proportion of the overall population each group represents from 1992 to 2004.

Marked disparities in disease distribution among sex-specific groups were even more striking. Asian men accounted for 19.4% of all cases of hepatocellular carcinoma while making up only 5.2% of the total population. A similar finding was observed among black men.

Liver Cancer Classification Differences 

Differences in classification over time (or between demographic groups) may artificially create differences in incidence rates. If 1 group, for example, was more likely to have liver cancers designated as “hepatocellular carcinomas” because of more aggressive histologic verification, that group may have a higher apparent incidence rate. We evaluated the classification differences of 4 categories of liver cancers by sex and race/ethnicity: malignant neoplasm/tumor, not otherwise specified; carcinoma, not otherwise specified; adenocarcinoma, not otherwise specified; and hepatocellular carcinoma (Table 2). Among men and women (combined), the 3 categories of unspecified/poorly differentiated cancers accounted for 13.8% of all liver cancers; the lowest and highest rates were in Asians (8.7%) and American Indian/Alaskans (20.6%). The poorly differentiated cancers accounted for 10.9% cancers among men and 17.4% of cancers among women (Table 2).

Table 2. Liver Cancer Classification Differences by Sex and Race/Ethnicity
Malignant Neoplasm/Tumor, NOS Rate (%)Carcinoma, NOS Rate (%)Adenocarcinoma, NOS Rate (%)Hepatocellular Carcinoma Rate (%)All Liver CA Rate (%)
Male
Caucasian0.2(3.8)0.3(5.7)0.2(3.8)4.3(81.1)5.3(100)
Black0.3(2.8)0.4(3.8)0.2(1.9)9.2(86.8)10.6(100)
American Indian/Alaskan0.4(4.7)0.5(5.8)0.4(4.7)6.6(76.7)8.6(100)
Asian or Pacific Islander0.7(3.6)0.5(2.5)0.3(1.5)17.5(88.8)19.7(100)
White Hispanic0.5(3.8)0.6(4.6)0.2(1.5)11.1(85.4)13(100)
Female
Caucasian0.1(5.6)0.1(5.6)0.1(5.6)1.2(66.7)1.8(100)
Black0.3(9.1)0.2(6.1)0.1(3.0)2.5(75.8)3.3(100)
American Indian/Alaskan0.5(10.9)0.4(8.7)0.2(4.3)3.2(69.6)4.6(100)
Asian or Pacific Islander0.4(5.8)0.3(4.3)0.2(2.9)5.7(82.6)6.9(100)
White Hispanic0.3(6.5)0.3(6.5)0.1(2.2)3.4(73.9)4.6(100)

Table 2 lists the average incidence rates of unspecified or poorly differentiated liver cancers compared with rates of hepatocellular carcinoma and all liver cancers from 1992-2004. The percent of all liver cancers each group represents is listed in parentheses. Annual incidence rates were age- standardized to U.S. population of 2000. NOS: not otherwise specified.

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Discussion 

Hepatocellular carcinoma is an increasing public health problem; increasing incidence coupled with poor survival has been observed in many countries, including the United States.3, 4, 5, 6, 7, 8, 10, 11, 12, 13 Our detailed analysis of age-specific, sex-specific, and race/ethnicity-specific variations in hepatocellular carcinoma incidence provides data needed to guide efforts at improving early detection and cancer management.

The key differences in cancer incidence rates based on sex, race/ethnicity, and age suggest that research and guidelines for disease prevention in the United States might require additional tailoring to risk profiles. Although no randomized trials or high-quality observational studies of hepatocellular carcinoma screening in the United States exist, indirect data on improved survival of patients treated for localized disease led to the creation of guidelines for screening in high-risk populations.19 On the basis of recent data (much of which are derived from Asian countries with different natural histories of diseases), the American Association for the Study of Liver Diseases (AASLD) recommends initiating screening in 2 broad categories: chronic hepatitis B carriers and patients with non-hepatitis B-related cirrhosis (typically from hepatitis C or alcohol use).16 Among hepatitis B carriers, the AASLD recommends screening in cirrhotic patients, patients with a family history of hepatocellular carcinoma, Asian men beginning at age 40 years, and Asian women beginning at age 50 years. Chronic hepatitis B carriers have significantly elevated risks of developing cancer compared with the general population. Although chronic hepatitis B in the United States is mostly a disease of immigrants, studies have shown differences in cancer risks in Asians, in whom the hepatitis B infection is likely acquired early in life compared with North American indigents, in whom infection is more frequently acquired later.25, 26, 27, 28, 29, 30, 31

In our study, Asians had by far the highest incidence rate of hepatocellular carcinoma, with men representing the majority of the cases (Table 1). Incidence rates in Asian men doubled approximately every 10 years, beginning at age 30 years (Figure 1). Differences in cause (hepatitis B infection early in life) likely contribute to these findings, suggesting hepatitis B as the major cause of hepatocellular carcinoma in this group.15, 20 Although the incidence rate in Asian men was more than triple that of women (Table 1), women reached male-comparable rates 15 years later for the earlier age groups, and at age 75 years the incidence rate among Asian men was still double that of Asian women (81.7 vs 35.8 per 100,000/y; P<.0001) (Figure 1). The finding that rates of hepatitis B infection among Asian men are approximately double that of Asian women may contribute to the observed gender differences in cancer incidence.32, 33, 34, 35 Chronic hepatitis B infection is an important predictor of cancer risk. The marked disparity in increasing cancer incidence among Asians suggests that more attention is needed toward screening and surveillance among patients with hepatitis B, especially among Asians.

In patients without hepatitis B, the AASLD recommends screening when there is evidence of cirrhosis.16 Sex-specific differences in these patients may represent differences in other risk factors (eg, hepatitis C and alcohol use) between men and women. Recent studies have reported rates of hepatitis C infection in blacks double that of Caucasians; the relationship between white Hispanics and other ethnic groups is less clear.36, 37, 38 In our study, the incidence rate of hepatocellular carcinoma in blacks was double that of Caucasians; the rate in white Hispanics tripled that of Caucasians (Table 1). Calendar year trends demonstrated a significant increase in cancer rates, with the greatest absolute increase among white Hispanics (Figure 2). Among these ethnic groups, cancer rates in men were triple that of women, with women reaching male-comparable rates more than a decade later (Figure 1). Although earlier exposure to risk factors may contribute to the observed differences in cancer incidence, the cause behind the stark gender differences remains unclear.15, 19, 39, 40, 41, 42

Patients with chronic hepatitis C and established cirrhosis have an annual cancer incidence of 2% to 8%; patients with hepatitis C without cirrhosis have lower risks of developing cancer.16, 43 Although chronic hepatitis B accounts for the majority of hepatocellular carcinoma cases in Asians, hepatitis C is found more often in Caucasians and blacks.15, 20 Among groups in whom hepatitis C is suggested to be predominant, our study demonstrates the cancer incidence among men increases more than a decade earlier than among women. The idea that genetics may combine with multiple risk factors in a synergistic carcinogenic relationship make a generalized approach to identifying patients for screening less effective. These findings suggest that an individualized approach to research and guidelines in cancer surveillance would benefit from incorporating the marked age-specific, race-specific, and gender-specific disparities observed.

A major limitation for the establishment of screening and surveillance programs is the relative paucity of high-quality data demonstrating that these interventions decrease mortality. No randomized trials or high-quality case-control studies exist in the United States or similar populations, although indirect data suggest the detection and treatment of early cancers increases the probability of survival.44, 45, 46, 47 The current analyses suggest the relative impact of screening for hepatocellular carcinoma may differ markedly within different demographic groups. Although Caucasians represent the majority of cancer cases, the relative burden of disease distribution identifies striking discrepancies. Asians represent approximately 11% of the overall population, but this group accounts for 27% of cancer cases (Figure 3). In addition, women represent approximately half of the population, but account for less than a quarter of cancer cases. The burden of disease each group carries is directly correlated with the relative benefit achieved per unit of health care resources expended. If screening is effective, the current data suggest that screening (for both viral hepatitis and hepatocellular carcinoma) may decrease the burden of disease the most among Asians and men.

The strengths of this study include the use of population-based data from a registry that covers a large proportion of the US population and is globally recognized as an authoritative source of information on cancer incidence and survival in the United States.10

Weaknesses of this study include the limited available data for identifiable risk factors, namely, hepatitis B and hepatitis C infection status, which preclude the calculation of disease-specific cancer rates. A concern when evaluating differences in incidence rates is whether reported disparities merely represent more accurate classification of disease. Although we found some differences by sex and race/ethnicity, differences in disease classification did not explain the variations observed.

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Conclusions 

Our study describes marked differences in hepatocellular carcinoma incidence by sex, ethnicity, and age of diagnosis. The fact that Asians and Hispanics are the fastest growing populations in the United States underscores the need to address the significantly higher rates of hepatocellular carcinoma in these groups.48 These disparities likely represent variations in risk factor distributions (eg, viral hepatitis), and possibly in host genetics or other environmental factors. The possibility that groups with similar identifiable risk factors can present with significantly different disease risk suggests that, if screening is effective, an individualized approach may more efficiently identify treatable tumors than more general guidelines, while minimizing interventions on patients with relatively lower risks of progressing to cancer. More studies are needed to determine disease-specific variations in cancer risks (eg, hepatitis B and C) and whether incorporating the variations observed into surveillance protocols is clinically efficacious.

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PII: S0002-9343(08)00248-9

doi:10.1016/j.amjmed.2008.03.005

The American Journal of Medicine
Volume 121, Issue 6 , Pages 525-531, June 2008

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